Leukocyte dynamics in mice and men

Abstract

Our limited knowledge of the expected life spans of granulocytes and T cells during health and disease hampers our understanding of the functioning of the immune system. Using stable isotope labeling we estimated the average life spans of human circulating granulocytes to be 6 days. This estimate was 10-fold higher than suggested in previous reports, supporting the emerging concept that neutrophils participate in complex long-term processes, such as immune regulation and recirculation. Since life span estimates of kinetically heterogeneous cell populations is labeling-time dependent, a new modeling strategy was introduced to fit average life spans independent of the labeling period. Deuterium labeling in human adults revealed a low daily production of naive T cells. Whereas naive T cells lived on average 6.0 (naive CD4+) and 9.4 years (naive CD8+), the few naive T cells that were recently produced had an even longer life expectancy. These data are incompatible with the existence of a substantial short-lived population of recent thymic emigrants in human adults. In contrast, a considerable thymic output was observed in mice. In addition, thymic emigrants lived as long as the average murine naive T cell in the periphery (48 and 83 days for naive CD4+ and CD8+ T cells, respectively), suggesting that the murine naive T-cell pool is kinetically homogeneous, which is incompatible with the co-existence of short-lived thymic emigrants and long-lived truly naive T cells. The different life expectancy of recently produced naive T cells in adult mice and men suggests different homeostatic mechanisms of naive T cells in the two species. Indeed, thymectomy experiments and TREC analyses in ageing mice revealed that almost all murine naive T cells represent thymic emigrants, whereas TREC analysis in ageing humans strongly suggests that the majority of newly produced human naive T cells is derived from peripheral proliferation. Since the mechanism of naive T-cell maintenance is fundamentally different in mice and men, this will influence the diversity of the TCR repertoire of the species. The difference in naive T-cell dynamics suggests that laboratory mice, which are worldwide used as a model to study T-cell dynamics in men, are not a good model to study naive T-cell homeostasis in humans. Chronic immune activation in HIV-1 infection plays an important role in CD4+ T-cell depletion. Using CD70Tg mice, we showed that even in the context of substantial thymic output, like in young children, chronic immune activation can lead to severe naive T-cell depletion. In human adults with a much lower thymic output, even moderately enhanced priming rates may lead to severe T-cell depletion. Collectively, these data shed a new light on the dynamics of granulocytes and T cells and point to a serious limitation regarding extrapolation of insights from mouse to man and vice versa.